Nitrogen-containing heterocyclic compounds

ABSTRACT

Novel nitrogen-containing heterocyclic compounds shown by the formula ##STR1## wherein Y represents an oxygen atom, a sulfur atom, or a group shown by ##STR2## (wherein m is 1 or 2); n represents 0 or 1; R 1  and R 4 , which may be the same or different, each represents a hydrogen atom, a lower alkyl group, or a lower alkenyl group; R 2  and R 3 , which may be the same or different, each represents a hydrogen atom, a hydroxyl group, a lower alkanoyloxy group, a lower alkyl group or a lower alkenyl group; said R 2  and R 3  may further form together a double bond; R 5  and R 6 , which may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a lower alkoxy group, a mono or di lower alkylamino group, or a lower alkyl group; said R 5  and R 6  may further form together a lower alkylenedioxy group; and R 7  represents a hydrogen atom, a halogen atom, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a lower alkyl group, a hydroxy lower alkyl group, a di lower alkylamino lower alkyl group, a pyrrolidino lower alkyl group, a piperidino lower alkyl group, a morpholino lower alkyl group, or a 4-lower alkylpiperazino lower alkyl group; 
     (1) when said R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are hydrogen atom and n is 0, said Y is a group shown by ##STR3## and (2) when said R 1 , R 2 , R 3 , R 4  and R 7  are hydrogen atom, at least one of said R 5  and R 6  is the aforesaid group other than hydrogen atom, and n is 0, said Y is oxygen atom or a group shown by ##STR4## and the pharmacologically acceptable non-toxic salts thereof. The compounds are strong analgesic anti-inflammatory agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel nitrogen-containing heterocycliccompounds. More particularly, the invention relates to thenitrogen-containing heterocyclic compounds shown by the formula I##STR5## wherein Y represents an oxygen atom, a sulfur atom, or a groupshown by ##STR6## (wherein m is 1 or 2); n represents 0 or 1; R₁ and R₄,which may be the same or different, each represents a hydrogen atom, alower alkyl group, or a lower alkenyl group; R₂ and R₃, which may be thesame or different, each represents a hydrogen atom, a hydroxyl group, alower alkanoyloxy group, a lower alkyl group or a lower alkenyl group;said R₂ and R₃ may further form together a double bond; R₅ and R₆, whichmay be the same or different, each represents a hydrogen atom, a halogenatom, a hydroxyl group, a nitro group, an amino group, a lower alkoxygroup, a mono or di lower alkylamino group, or a lower alkyl group; saidR₅ and R₆ may further form together a lower alkylenedioxy group; and R₇represents a hydrogen atom, a halogen atom, a lower alkanoyl group, aphenyl group, a phenyl lower alkyl group, a lower alkyl group, a hydroxylower alkyl group, a di lower alkylamino lower alkyl group, apyrrolidino lower alkyl group, a piperidino lower alkyl group, amorpholino lower alkyl group, or a 4-lower alkylpiperazino lower alkylgroup;

(1) when said R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are hydrogen atom and n is0, said Y is a group shown by ##STR7## and (2) when said R₁, R₂, R₃, R₄and R₇ are hydrogen atom, at least one of said R₅ and R₆ is theaforesaid group other than hydrogen atom, and n is 0, said Y is oxygenatom or a group shown by ##STR8## and the pharmacologically acceptablenon-toxic salts thereof.

Since the compounds of this invention shown by the formula I have verystrong anti-inflammatory activity and also strong analgesic activity,the compounds are used as strong analgesic anti-inflammatory agents.

The definitions of the terms used in the specification and the claims ofthis invention are as follows:

That is, "lower alkyl group" is a straight or branched chain alkyl grouphaving 1-6 carbon atoms and includes, for example, methyl, ethyl,porpyl, isopropyl, n-butyl, isobutyl, n-butyl, sec-butyl, tert-butyl,amyl, isoamyl, and n-hexyl groups. "Lower alkenyl group" is a straightor branched chain alkenyl group having 2-6 carbon atoms and includes,for example, vinyl, allyl, and 2-butenyl groups. "Lower alkoxy group" isa straight or branched chain alkoxy group having 1-6 carbon atoms andincludes, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,amyloxy, and n-hexyloxy groups. "Lower alkylenedioxy group" is astraight chain alkylenedioxy group having 1-4 carbon atoms and includes,for example, methylenedioxy, ethylenedioxy, and porpylenedioxy groups."Lower alkanoyl group" is a straight or branched chain alkanoyl grouphaving 1-6 carbon atoms and includes, for example, formyl, acetyl,propionyl, butyryl, and isobutyryl groups. "Halogen atom" includesfluorine, chlorine, bromine, and iodine atoms. And, "phenyl lower alkylgroup" is a phenyl-substituted lower alkyl group and includes, forexample, benzyl and phenethyl groups.

The compounds of this invention shown by the formula I have a feature ofchemical structure in the point that the 2-position and the 3-positionof the 1-isoquinolone are cyclized by a hetero-atom (oxygen atom orsulfur atom) and an alkylene group and it has not hitherto been knownthat such nitrogen-containing heterocyclic compounds have excellentanti-inflammatory activity. In addition, as such nitrogen-containingheterocyclic compounds, 5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinolineshown by the formula ##STR9## wherein X represents a hydrogen atom, achlorine atom, a bromine atom, an alkyl group, an alkoxy group, analkylamino group, a dialkylamino group, an arylamino group, an acylaminogroup, an aryl group, or an aryloxy group and Y represents a hydrogenatom, a chlorine atom, a bromine atom, an alkyl group or an alkoxy groupis disclosed in Offenlegungsschrift No. 1,960,376 and also5-oxo-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline ##STR10## is disclosedin "Ann. Chemie, 729, 83-96(1969)" as intermediates for dyes in bothcases. However, there are no descriptions about the usefulness of thesecompounds as medicaments in the literatures.

The preferred homologues of the compounds of this invention are thenitrogen-containing heterocyclic compounds of furmula I wherein Y is asulfur atom or the group shown by ##STR11## and each of R₂ and R₃ is ahydrogen atom or a lower alkyl group. Other preferred homologues of thecompounds of this invention are the nitrogen-containing heterocycliccompounds of formula I wherein Y is an oxygen atom and each of R₂ and R₃is a hydrogen atom or a lower alkyl group.

Examples of the particularly preferred compounds of this invention are

6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline

6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide

6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide

8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline

8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide

7-chloro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1-oxide

7-chloro-3-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline

7-chloro-3-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1-oxide

7-chloro-5-oxo-2,3-dihydro-5H-ozazolo[3,2-b]isoquinoline

8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-oxazino[3,2-b]isoquinoline

11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline

11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxideand

11-formyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline

As the phamacologically acceptable non-toxic salts of the compounds ofthis invention shown by formula I, there are the addition salts of anacid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, etc.

The compounds of this invention shown by the formula I can be preparedas follows:

(A). The compound of this invention shown by the formula I wherein Y isan oxygen atom or a sulfur atom and R₂ is a hydrogen atom or a loweralkyl group, that is the compound shown by the formula Ia ##STR12##wherein Y' represents an oxygen atom or a sulfur atom; R₂ ' represents ahydrogen atom, a lower alkyl group, or a lower alkenyl group; R₇ 'represents a hydrogen atom, a phenyl group, a phenyl lower alkyl group,a lower alkyl group, a di-lower alkylamino lower alkyl group, apyrrolidino lower alkyl group, a piperidino lower alkyl group, amorpholino lower alkyl group, or a 4-lower alkylpiperazino lower alkylgroup; and R₁, R₃, R₄, R₅, R₆ and n have the same significance as in theformula I; (1) when R₁, R₂ ', R₃, R₄, R₅, R₆ and R₇ ' are hydrogen atom,n is 1, and (2) when R₁, R₂ ', R₃, R₄ and R₇ ' are hydrogen atom, atleast one of R₅ and R₆ is the aforesaid group other than hydrogen atom,and n is 0, Y' is oxygen atom can be prepared by reacting the compoundshown by the formula II ##STR13## wherein A represents a carboxy groupor a cyano group; B represents a hydroxyl group or a lower alkoxy group;and R₅, R₆ and R₇ ' have the same significance as above; when A is acarboxy group, B is a hydroxyl group with the compound shown by theformula III ##STR14## wherein Y', R₁, R₂ ', R₃, R₄ and n have the samesignificance as above.

Practically, the compound the formula II is reacted with an equimolar orexcessive molar amount of the compound of the formula III in an organicsolvent which does not participate in the reaction in the presence of,as the case may be, an acid catalyst. In this case, it is preferred toperform the reaction under heating, that is, the reaction is preferablyperformed at a temperature near the boiling point of the solvent used oris performed at a temperature above the boiling point of the solvent ina sealed tube. The reaction is usually performed under refluxing. As anorganic solvent which does not participate in the reaction, there are,for example, methanol, ethanol, ether, 2-ethoxyethanol, diglyme,dimethylformamide, xylene, ethylene glycol, and dichlorobenzene. As theacid catalyst used in the reaction, there are, for example,p-toluenesulfonic acid and sulfuric acid. In addition, the compound ofthe formula II wherein A is a carboxy group may be supplied in thereaction system as the acid anhydride thereof and further the compoundof the formula III may be supplied as the addition salt of an acid suchas hydrochloric acid, hydrobromic acid, etc. When the acid addition saltof the compound of the formula III is used, the reaction is usuallyperformed in the presence of a base such as sodium acetate, sodiummethoxide, sodium ethoxide, etc.

In this case, when the reaction is performed in the absence of an acidcatalyst using the compound of the formula III wherein n is 1, thecompound shown by the formula IV ##STR15## wherein Y', R₁, R₂ ', R₃, R₄,R₅, R₆ and R₇ ' have the same significance as above can be obtained inthe case of using the compound of the formula II wherein A is a carboxygroup and by heating the compound of the formula IV in the presence ofan acid catalyst, the compound of the aforesaid formula Ia wherein n is1 can be obtained.

In addition, the intermediate compound of the formula IV wherein Y' is asulfur atom can also be obtained by reacting the compound of the formulaII wherein A is a carboxy group with the compound shown by the formula V##STR16## wherein R₁, R₂ ', R₃ and R₄ have the same significance asabove and then reacting the product with hydrogen sulfide, sodiumhydrosulfide, etc.

(B). The compound of this invention shown by the formula I wherein Y isa sulfur atom and R₂ is a hydrogen atom or a lower alkyl group, that isthe compound of this invention shown by the formula Ib ##STR17## whereinR₁, R₂ ', R₃, R₄, R₅, R₆, R₇ and n have the same significance as abovecan be prepared by reacting the compound shown by the formula VI##STR18## wherein R₅, R₆ and R₇ have the same significance as above withthe compound shown by the formula VII ##STR19## wherein R₁, R₂ ', R₃, R₄and n have the same significance as above. Practically, the compound ofthe formula VI is reacted with an equimolar or excessive molar amount ofthe compound of the formula VII in an organic solvent which does notparticipate in the reaction. In this case, it is preferred to performthe reaction in the presence of a base such as an alkali metal alkoxide,e.g., sodium methoxide, sodium ethoxide, etc. It is also preferred toperform the reaction under heating, that is the reaction is preferablycarried out at a temperature near the boiling point of the solvent usedor is carried out at a temperature above the boiling point of thesolvent in a sealed tube. Also, examples of the organic solvents whichdo not participate in the reaction are methanol, ethanol, ether,2-ethoxyethanol, diglyme, xylene, ethylene glycol, dichlorobenzene, etc.In addition, the compound of the formula VI may be supplied to thereaction system as the compound shown by the formula VIa ##STR20## orthe compound shown by formula VIb ##STR21## wherein R₅, R₆ and R₇ havethe same significance as above.

(C). The compound of this invention shown by the formula I wherein Y isthe group shown by ##STR22## can be prepared from the compound of theformula I wherein Y is a sulfur atom. That is, the compound of thisinvention shown by the formula Ic ##STR23## wherein R₁, R₂, R₃, R₄, R₅,R₆, R₇, m, and n have the same significance as above can be prepared byoxidizing the compound shown by the formula VIII ##STR24## wherein R₁,R₂, R₃, R₄, R₅, R₆, R₇ and n have the same significance as above.

Practically, the compound of the formula VIII is dissolved in an organicacid such as acetic acid and is reacted with an oxidizing agent undercooling or at room temperature, or under heating. Conventional oxidizingagents can be employed in the reaction. It is preferred to use 10-40%aqueous hydrogen peroxide solution as the oxidizing agent. In this case,by properly selecting the reaction conditions such as the reaction time,the reaction temperature, the amount of the oxidizing agent, etc., thedesired monoxide compound (m=1) or as the desired dioxide compound (m=2)can be obtained.

(D). The compound of this invention shown by the formula I wherein R₂and R₃ for together a double bond can be prepared from the compound ofthe formula I wherein one of R₂ and R₃ is a hydroxyl group or a loweralkanoyloxy group and the other is a hydrogen atom. That is, thecompound of this invention shown by the formula Id ##STR25## wherein Y,R₁, R₄, R₅, R₆, R₇ and n have the same significance as above can beprepared by treating the compound shown by the formula IX with an acid##STR26## wherein one of R₂ " and R₃ ' is a hydroxyl group or a loweralkanoyloxy group and the other is a hydrogen atom, and Y, R₁, R₄, R₅,R₆, R₇ and n have the same significance as above.

Practically, the acid treatment is usually performed at room temperatureusing an acid such as concentrated sulfuric acid, phosphoric acid, etc.In this case, a solvent such as ethanol, etc., may be used. Furthermore,the reaction may be also carried out by heating the compound in anorganic solvent using p-toluenesulfonic acid, etc.

(E). The compound of this invention shown by the formula I wherein Y isa sulfur atom and R₂ is a lower alkanoyloxy group can be prepared fromthe compound of the formula I wherein Y is the group shown by ##STR27##(wherein m is 1) and R₂ is a hydrogen atom. That is, the compound ofthis invention shown by formula Ie ##STR28## wherein R₁, R₃, R₄, R₅, R₆and n have the same significance as above can be prepared by reactingthe compound shown by the formula X ##STR29## wherein R₁, R₃, R₄, R₅, R₆and n have the same significance as above with an acylating agent suchas acetic anhydride, etc. In this case, when R₃ is a hydrogen atom inthe compound of the formula Ie thus obtained, the compound of Id whereinY is a sulfur atom can be obtained by treating the compound with an acidaccording to the method (D) without isolating the compound from thereaction mixture.

(F). The compound of the formula I wherein R₂ and/or R₃ is a hydroxylgroup can be prepared by hydrolyzing the compound of the formula Iwherein R₂ and/or R₃ is a lower alkanoyloxy group under an alkalinecondition according to a conventional manner.

(G). The compound of this invention shown by the formula I wherein R₂and/or R₃ is a lower alkanoyloxy group can be prepared by acylating thecompound of the formula I wherein R₂ and/or R₃ is a hydroxyl group witha corresponding acylating agent such as acetic anhydride, etc.,according to a conventional manner.

(H). The compound of this invention shown by the formula I wherein R₅and/or R₆ is an amino group can be prepared by catalytic reducing thecompound of the formula I wherein R₅ and/or R₆ is a nitro groupaccording to a conventional manner.

(I). The compound of this invention shown by the formula I wherein R₅and/or R₆ is a nitro group can be prepared by nitrating the compound ofthe formula I wherein at least one of R₅ and R₆ is a hydrogen atom withnitric acid according to a conventional manner.

(J). The compound of this invention shown by the formula I wherein R₇ isa halogen atom can be prepared by halogenating the compound of theformula I wherein R₇ is a hydrogen atom with a halogen such as chlorine,bromine, etc., according to a conventional manner.

(K). The compound of this invention shown by the formula I wherein R₇ isa lower alkanoyl group can be prepared by acylating the compound of theformula I wherein R₇ is a hydrogen atom with a corresponding acyl halidesuch as acetyl chloride, etc., according to a conventional manner. Inaddition, the compound of the formula I wherein R₇ is a formyl group canalso be prepared by reacting the compound of the formula I wherein R₇ isa hydrogen atom with a complex of dimethylformamide and phosphorusoxychloride (Vilsmeier reagent) followed by hydrolysis.

(L). The compound of this invention shown by the formula I wherein R₇ isa hydroxymethyl group can be prepared by reducing the compound of theformula I wherein R₇ is a formyl group according to a conventionalmanner.

(M). The compound of this invention shown by the formula I wherein R₇ isa di-lower alkylaminomethyl group, a pyrrolidinomethyl group, apiperidinomethyl group, a morpholinomethyl group, or a 4-loweralkylpiperazinomethyl group can be prepared from the compound of formulaI wherein R₇ is a hydrogen atom by a Mannich reaction, that is, byreacting the compound with formaldehyde and a corresponding amine(di-lower alkylamine, etc.,) according to a conventional manner.

(N). The compound of this invention shown by the formula I wherein R₇ isa di-lower alkylaminoalkyl group, a pyrrolidino lower alkyl group, apiperidino lower alkyl group, a morpholino lower alkyl group, or a4-lower alkylpiperidino lower alkyl group can be prepared byhalogenating the compound of the formula I wherein R₇ is a hydroxy loweralkyl group to form the compound of the formula I wherein R₇ is ahalogeno lower alkyl group and then reacting the product with acorresponding amine (di-lower alkylamine, etc.,) according to aconventional manner.

(O). The compound of this invention shown by the formula I wherein Y isthe group shown by ##STR30## (wherein m is 2) and at least one of R₁ andR₂ is a lower alkyl group or a lower alkenyl group can be prepared byreacting the compound of the formula I wherein Y is the group shown by##STR31## (wherein m is 2) and R₁ and R₂ are a hydrogen atom and acorresponding lower alkylhalide or a lower alkenylhalide in the presenceof a strong base such as sodium amide, potassium amide, etc., accordingto a conventional manner.

The compounds of this invention shown by the formula I thus prepared canbe isolated and purified by an ordinary chemical treatment such asconcentration, recrystallization, column chromatography, etc.

Then, the results of the following experiments show the excellenttherapeutical activities of the compounds of this invention:

(a) Carrageenin-induced edema

Male Wister rats (weighting 130-170 g.), one group being 6 rats, fastedovernight were used. According to Winter's method [Proc. Soc. Exp. Biol.Med., 111,544 (1962)], 0.1 ml. of 1% carrageenin [Iwai Kagaku Yakuhin K.K. Seakem] suspension in 0.9% saline was injected into the plantertissue of the left hind paw. After 3 hours, each rat was sacrificed bychloroform and the hind paw was cut and weighed immediately. By usingthe value obtained by subtracting the weight of the untreated hind pawfrom the weight of the hind paw having injected thereto the carrageeninas the weight of edema, the inhibitory ratio of the sample administeredrat groups to control groups was calculated. The sample was orallyadministered before one hour of the injection of carrageenin. Theresults obtained are shown in Table 1.

(b) Whittle's method (British J. Pharmacol.; 22, 246-253 (1964))

Male ICR-Mice (weighting 25-35 g.), one group being 12 mice, fastedovernight were used in this test. The sample was orally administered,and 20 minutes after, 5 ml./Kg. of 0.4% Evance blue was injectedintravenously and further 10 minutes after, 10 ml./Kg. of 0.6% aceticacid was injected intraperitoneally. The number of writhings after 20minutes since the administration of acetic acid was recorded and further10 minutes after since then, the mice were killed by dislocation of theneck, the dye leaked in the abdominal cavity was washed out with 5 ml.of 0.9% saline to make the total amount 10 ml., and thereafter furs,blood corpuscles, etc., intermingled were removed by centrifugalseparation at 3,000 r.p.m. for 5 minutes. Furthermore, for preventingturbidity caused by protein, 0.1 ml. of an aqueous 0.1 normal sodiumhydroxide was added and then the absorbance at 590 nm was measured. Theinhibition ratio of the sample administered rat groups to control groupswas calculated. The results are shown in Table 2.

(c) Antipyretic effect

Male Wister rats (weighting 130-150 g.), one group being 5 rats, wereused. Hyperthermia was caused by subcutaneous injection of 2 ml./rat of20% Brewer's yeast suspension. 18 hours later, the rats showing a risein temperature exceeding 1° C. were selected and allocated into groupseach consisting of 5 rats. The sample was orally administered and thenthe body temperature was measured with the passage of time for 6 hourssince then. In addition, the body temperature was measured by measuringthe temperature in the rectum by means of a thermister thermometer. Theresults are shown in Table 3.

(d) Acute toxicity

Male Wister rats (weighting 130-170 g.), one group being 5 rats, fastedovernight were used in this test. After orally administering 500 mg./Kg.of a sample, they were observed for 7 days to determine whether theywere living or dead. The results are shown in Table 4.

In addition, the test samples used in the aforesaid tests (a), (b), (c)and (d) were prepared by suspending the test compounds, in the cases ofusing the compounds of Test Nos. 1-12 and phenylbutazone, in an aqueous0.5% methyl cellulose solution, dissolving the test compounds, in thecases of using aminopyrine, in distilled water.

                  Table 1                                                         ______________________________________                                        (Carrageenin-induced edema)                                                                                        Inhibi-                                  Test                        Dose     tion                                     No.    Sample               (mg/kg)  (%)                                      ______________________________________                                              ##STR32##             25 50    54.8 69.8                                2                                                                                   ##STR33##             25 50    41.7 71.2                                3                                                                                   ##STR34##             25 50    47.0 74.0                                4                                                                                   ##STR35##             25 50    41.2 65.1                                5                                                                                   ##STR36##             25 50    55.3 67.2                                6                                                                                   ##STR37##             25       57.1                                     7                                                                                   ##STR38##             25       57.0                                     8                                                                                   ##STR39##             25       57.5                                     9                                                                                   ##STR40##             25       53.4                                     10                                                                                  ##STR41##             25       58.0                                     11                                                                                  ##STR42##             25       45.9                                     12                                                                                  ##STR43##             50       71.3                                          Phenylbutazone         25       29.4                                                                 50       44.5                                     ______________________________________                                    

                  Table 2                                                         ______________________________________                                        (Whittle's method)                                                                    Inhibition (%)                                                                Writhings   Permeability                                                        25mg/    50mg/    25mg/  50mg/                                      Sample    kg P.O.  kg P.O.  kg P.O.                                                                              kg P.O.                                    ______________________________________                                        Compound of                                                                   Test No.                                                                             1      24.8     57.8   26.2   21.3                                     "      2      22.6     14.4    4.7   20.1                                     "      3      --       67.5   --     37.0                                     "      4      29.1     39.7   22.1   41.1                                     "      5      12.9     58.6   22.6   36.0                                     "      6      --       28.8   --     37.1                                     "      7      --       69.5   --     38.6                                     "      8      --       74.3   --     23.5                                     "      9      --       82.9   --     34.1                                     "      10     --       91.6   --     32.4                                     Aminopyrine                                                                             29.6     58.1     28.5   41.7                                       ______________________________________                                    

                                      Table 3                                     __________________________________________________________________________    (Antipyretic effect)                                                                 Dose Rectal temperature (mean±SE)                                   Sample (P.O.)                                                                             before                                                                              1 hour 2 hours                                                                              4 hours                                                                              6 hours                                __________________________________________________________________________    Compound of                                                                   Test No. 1                                                                           50mg/kg                                                                            39.26±0.19                                                                       *38.72±0.13                                                                       *38.20±0.15                                                                       *37.39±0.23                                                                       *37.44±0.32                         Test No. 2                                                                           "    38.94±0.14                                                                       39.04±0.23                                                                        38.41±0.21                                                                        *37.32±0.31                                                                       *37.55±0.33                         Aminopyrine                                                                          "    39.24±0.14                                                                       *37.92±0.09                                                                       *37.49±0.10                                                                       *37.39±0.07                                                                       *37.76±0.19                         0.9% saline                                                                          10ml/kg                                                                            39.06±0.16                                                                       39.56±0.32                                                                        39.28±0.23                                                                        39.11±0.16                                                                        39.31±0.19                          __________________________________________________________________________     [*: significantly different from the temperature before administration        (P<0.05) ]-                                                              

                  Table 4                                                         ______________________________________                                        (Acute toxicity)                                                              Sample          Number of death Mouse                                         ______________________________________                                        Compound of Test No.                                                                        1     1/5                                                       "             2     0/5                                                       "             3     3/5                                                       "             4     3/5                                                       "             5     3/5                                                       ______________________________________                                    

From the test results by the aforesaid Carrageenin-induced edema andWittle's method, it is clear that the compounds I of this invention haveexcellent anti-inflammatory activity and excellent analgesic activity.Furthermore, from the results by the antipyretic effect, it is alsoclear that the compounds of this invention shown by formula I haveexcellent antipyretic activity.

The clinical doses of the compounds I of this invention are usually100-1,000 mg., preferably 150-600 mg. per day for an adult and themedicament is administered 2-3 times per day. The doses are properlycontrolled according to the condition and age of the patient.

The compounds of this invention are administered as various forms suchas agents for oral administration, injections, suppositories for rectaladministration, medicines for topical application, etc.

The medicaments of this invention are used as compositions prepared byblending with conventional pharmaceutical carriers or excipients byordinary method. The tablets, capsules, granules, powders, etc., of thecompounds of this invention for oral administration may contain anpharmaceutical excipient generally used in the field of art, such ascalcium carbonate, calcium phosphate, starch, sucrose, lactose, talc,magnesium stearate, gelatin, polyvinyl pyrrolidone, gum arabic,sorbitol, microcrystalline cellulose, polyethylene glycol, silica,sodium laurylsulfate, etc. Moreover, the tablets may be coated by amanner well known in the art.

Furthermore, the liquid formulations for oral administration may be anaqueous or oily suspeison, a syrup, an elixir, etc., and are prepared bya conventional method.

Suppositories for rectal use are used and they may contain a formulationcarrier well known in the art, such as polyethylene glycol, lanolin,cacao butter, Witepsol® (made by Dynamite Nobel Co.), etc.

Then, examples of the formulations of the medicaments of this inventionare shown below:

FORMULATION EXAMPLE 1:

Tablets containing the compounds of this invention shown by formula I,the weight of one tablet being 300 mg.

    ______________________________________                                        Compound of formula I 1,000 g.                                                Lactose               1,200 g.                                                Starch                770 g.                                                  Magnesium stearate    30 g.                                                   ______________________________________                                    

A 10% starch paste was prepared using a part of starch described aboveand after adding the starch paste as a binder to a mixture of thecompounds of formula I, lactose and remaining starch, the resultantmixture was granulated by a conventional manner. Then, magnesiumstearate was added to the granules and the mixture was molded into10,000 tablets each having a diameter of 9.5 mm. and weight of 300 mg.The active component was 100 mg./tablet.

FORMULATION EXAMPLE 2:

Capsules containing the compounds I of this invention, the weight of onecapsule being 300 mg.

    ______________________________________                                        Compound of formula I 1,000 g.                                                Lactose               1,200 g.                                                Starch                770 g.                                                  Magnesium stearate    30 g.                                                   ______________________________________                                    

After mixing well 1,000 g. of the compound of formula I, 1,200 G. oflactose, 770 g. of starch, and 30 g. of magnesium stearate, the mixturewas filled in 10,000 capsules. The weight of each capsule filled withthe mixture was 300 mg. The active component was 100 mg./capsule.

EXAMPLE 1 ##STR44##

In 10 ml. of acetic acid were dissolved 3.6 g. of 2-carboxymethylbenzoicacid and 1.3 g. of 2-aminopropanethiol.hydrochloride and after furtheradding 3.3 g. of sodium acetate to the solution, the resultant mixturewas refluxed for 3 hours. After the reaction was over, the reactionmixture was cooled, poured into 50 ml. of ice water, and extracted threetimes each time with 20 ml. of ethyl acetate. The extracts were combinedwith each other, washed with a 10% aqueous sodium carbonate solution andwater, and after drying over anhydrous magnesium sulfate, the solventwas distilled off. The crystals formed were recovered and recrystallizedfrom ethanol to provide 1.1 g. of3-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline.

Melting point 83°-84° C.

Elemental analysis for C₁₂ H₁₁ NSO:

    ______________________________________                                                  C      H        N        S                                          ______________________________________                                        Found:      66.20%   4.84%    6.51%  14.27%                                   Calculated: 66.33%   5.10%    6.45%  14.75%                                   ______________________________________                                    

EXAMPLE 2 ##STR45##

In 10 ml. of o-dichlorobenzene were dissolved 3.6 g. of2-carboxymethylbenzoic acid and 1.5 g. of 3-aminopropanol and afterrefluxing the solution for 4 hours,, 100 mg. of p-toluenesulfonic acidwas added to the solution followed by further refluxing for 3 hours.After the reaction was over, the reaction mixture was cooled, applied toa silica gel column chromatography using 30 g. of silica gel, purifiedby a mixture of ethanol and chloroform (1:99 by volume ratio), and thecrude crystals obtained were recrystallized from ethanol to provide 0.7g. of 6-oxo-2,3-dihydro-2H,6H-1,3-oxazino[3,2-b]isoquinoline.

Melting point 100°-101° C.

Elemental analysis for C₁₂ H₁₁ NO₂ :

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      71.61%     5.53%      6.85%                                       Calculated: 71.63%     5.51%      6.96%                                       ______________________________________                                    

EXAMPLE 3 ##STR46##

In 20 ml. of o-dichlorobenzene were dissolved 7.2 g. of2-carboxymethylbenzoic acid and 5.2 g. of 3-aminopropanethiolhydrochloride and after adding 6.6 g. of sodium acetate to the solution,the resultant mixture was refluxed for 3 hours. The precipitates thusformed were filtered off and 3 g. of p-toluenesulfonic acid was added tothe filtrate followed by refluxing for one hour. After the reaction wasover, the reaction mixture was cooled, applied to a silica gel columnchromatography using 80 g. of silica gel, and purified by a mixture ofethanol and chloroform (1:99 by volume ratio). The fractions containingthe desired product were collected, the solvent was distilled off, andthe crude crystals obtained were recrystallized from ethanol to provide3.0 g. of 6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 85°-86° C.

Elemental analysis for C₁₂ H₁₁ NSO:

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   66.16%  4.91%       6.22% 14.58%                                     Calculated:                                                                            66.33%  5.10%       6.45% 14.75%                                     ______________________________________                                    

EXAMPLE 4 ##STR47##

In 10 ml. of acetic acid was dissolved 1.0 g. of5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline and after adding 0.68g. of a 30% aqueous hydrogen peroxide solution to the solution underice-cooling, the resultant mixture was allowed to stand overnight atroom temperature. The reaction mixture obtained was concentrated underreduced pressure and the crude crystals formed were recovered andrecrystallized from 20 ml. of ethanol to provide 650 mg. of5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1-oxide.

Melting point 160°-162° C.

Elemental analysis for C₁₁ H₉ NSO₂ :

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   60.28%  4.07%       6.33% 14.56%                                     Calculated:                                                                            60.26%  4.14%       6.39% 14.62%                                     ______________________________________                                    

EXAMPLE 5 ##STR48##

In one ml. of acetic acid was dissolved 50 mg. of5-oxo-5H-thiazolo[3,2-b]isoquinoline and after adding 0.05 ml. of a 30%aqueous hydrogen peroxide solution to the solution, the resultantmixture was heated to 80° C. for 8 hours. After the reaction was over,the reaction mixture was cooled and the crystals precipitated wererecovered to provide 35 mg. of5-oxo-5H-thiazolo[3,2-b]isoquinoline-1,1-dioxide.

Melting point 256°-260° C.

Elemental analysis for C₁₁ H₇ NSO₃

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   56.43%  3.25%       5.82% 14.01%                                     Calculated:                                                                            56.64%  3.03%       6.01% 13.75%                                     ______________________________________                                    

EXAMPLE 6 ##STR49##

In 10 ml. of acetic acid was dissolved 1.65 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline and after adding0.84 g. of a 30% aqueous hydrogen peroxide solution to the solution, theresultant mixture was treated as in Example 4 to provide 900 mg. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide.

Melting point 132°-133° C.

Elemental analysis for C₁₂ H₁₁ SNO₂ :

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   61.85%  4.36%       5.67% 13.47%                                     Calculated:                                                                            61.78%  4.75%       6.00% 13.74%                                     ______________________________________                                    

EXAMPLE 7 ##STR50##

In 10 ml. of acetic acid was dissolved 0.8 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline and after adding0.84 g. of a 30% aqueous hydrogen peroxide solution, the resultantmixture was refluxed for 2 hours. After the reaction was over, thereaction mixture was concentrated under reduced pressure and the crudecrystals obtained were recrystallzed from 100 ml. of ethanol to provide550 mg. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 206°-208° C.

Elemental analysis for C₁₂ H₁₁ SNO₃ :

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   57.69%  4.32%       5.58% 12.72%                                     Calculated:                                                                            57.82%  4.45%       5.62% 12.86%                                     ______________________________________                                    

EXAMPLE 8 ##STR51##

By following the same procedure as in Example 7 using 1.0 g. of5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline and 1.4 g. of a 30%aqueous hydrogen peroxide solution, 550 mg. of5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1,1-dioxide wasobtained.

Melting point 208°-211° C.

Elemental analysis for C₁₁ H₉ NSO₃ :

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   56.04%  3.66%       5.85% 13.11%                                     Calculated:                                                                            56.16%  3.87%       5.95% 13.63%                                     ______________________________________                                    

EXAMPLE 9 ##STR52##

In 20 ml. of acetic anhydride were dissolved 2.0 g. of5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1-oxide and 0.2 g. ofsodium acetate and the solution was refluxed for 12 hours. Aftercooling, the reaction mixture obtained was poured into 200 ml. of waterand the crude crystals thus precipitated were recovered by filtrationand then recrystallized from 20 ml. of ethanol to provide 1.6 g. of2-acetoxy-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline.

Melting point 141°-143° C.

Elemental analysis for C₁₃ H₁₁ SNO₃ :

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   59.80%  4.09%       5.22% 12.05%                                     Calculated:                                                                            59.76%  4.24%       5.36% 12.27%                                     ______________________________________                                    

EXAMPLE 10 ##STR53##

In 5 ml. of concentrated sulfuric acid was dissolved 1.1 g. of2-acetoxy-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline and thesolution was allowed to stand for one hour at room temperature. Thereaction mixture obtained was added to 50 ml. of ice water and extractedthree times each time with 15 ml. of ethyl acetate. The extracts werecombined with each other and after washing with water, the extract wasdried over anhydrous magnesium sulfate. Then, the solvent was distilledoff under reduced pressure and the crude crystals obtained wererecrystallized from ethanol to provide 500 mg. of5-oxo-5H-thiazolo[3,2-b]isoquinoline.

Melting point 135°-136° C.

Elemental analysis for C₁₁ H₇ NSO:

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   65.39%  3.40%       6.69% 15.37%                                     Calculated:                                                                            65.65%  3.51%       6.96% 15.93%                                     ______________________________________                                    

EXAMPLE 11 ##STR54##

By following the same procedure as in Example 10 using 55 mg. of2-hydroxy-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline, 40 mg. of5-oxo-5H-thiazolo[3,2-b]isoquinoline was obtained.

Melting point 135°-136° C.

EXAMPLE 12 ##STR55##

In 5 ml. of methanol was dissolved 250 mg. of2-acetoxy-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline and afteradding 5 ml. of a 1 normal aqueous sodium hydroxide solution to thesolution, the resultant mixture was allowed to stand overnight at roomtemperature. The reaction mixture obtained was concentrated to about ahalf volume thereof and extracted three times each time with 5 ml. ofethyl acetate. The extracts were combined with each other and thesolvent was distilled off under reduced pressure. The crystals thusformed were recovered by filtration and recrystallized from 10 ml. ofethanol to provide 165 mg. of2-hydroxy-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline.

Melting point 215°-217° C.

Elemental analysis for C₁₁ H₉ NSO₂ :

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   60.01%  3.89%       6.36% 14.23%                                     Calculated:                                                                            60.26%  4.14%       6.39% 14.62%                                     ______________________________________                                    

EXAMPLE 13 ##STR56##

In 10 ml. of o-dichlorobenzene were dissolved 2.5 g. of2-carboxymethyl-5-chlorobenzoic acid and 2.2 g. of 3-aminopropanethiolhydrobromide and after further adding 1.0 g. of sodium acetate to thesolution, the resultant mixture was heated to 150°-160° C. for 2 hourswith stirring. Then, 2.0 g. of p-toluenesulfonic acid was added to thereaction mixture at 140°-150° C. followed by stirring for 20 minutes,the reaction mixture was cooled to room temperature. The precipitatesformed was filtered off and the filtrate was distilled under reducedpressure. To the residue formed was added isopropanol and the crystalsformed were recovered by filtration and recrystallized from isopropanolto provide 1.9 g. of8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 117°-118° C.

Elemental analysis for C₁₂ H₁₀ NOSCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  57.01%   3.98%   5.32%   12.84%                                                                              13.94%                                 Calculated:                                                                           57.26%   4.00%   5.56%   12.74%                                                                              14.08%                                 ______________________________________                                    

EXAMPLE 14 ##STR57##

In 3 ml. of glacial acetic acid was dissolved 500 mg. of8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andafter adding 0.23 ml. of a 30% aqueous hydrogen peroxide solution to thesolution under ice-cooling, the resultant mixture was allowed to standovernight at room temperature. The reaction mixture obtained was pouredin ice water and the crystals precipitated were recovered by filtrationand recrystallized from ethanol to provide 380 mg. of8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide.

Melting point 147°-148° C.

Elemental analysis for C₁₂ H₁₀ NO₂ SCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  53.61%   3.70%   4.99%   11.95%                                                                              13.27%                                 Calculated:                                                                           53.83%   3.76%   5.23%   11.98%                                                                              13.24%                                 ______________________________________                                    

EXAMPLE 15 ##STR58##

In 3 ml. of glacial acetic acid was dissolved 500 mg. of8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andafter adding 0.5 ml. of a 30% aqueous hydrogen peroxide solution to thesolution, the resultant mixture was heated to 70°-80° C. for 3 hours.After the reaction was over, the reaction mixture was cooled and thecrystals precipitated were recovered by filtration and recrystallizedfrom glacial acetic acid to provide 400 mg. of8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 234°-235° C.

Elemental analysis for C₁₂ H₁₀ NO₃ SCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  50.47%   3.45%   4.94%   11.56%                                                                              12.75%                                 Calculated:                                                                           50.80%   3.55%   4.94%   11.30%                                                                              12.50%                                 ______________________________________                                    

EXAMPLE 16 ##STR59##

In 5 ml. of glacial acetic acid was dissolved 475 mg. of7-chloro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline and afteradding 0.19 ml. of a 35% aqueous hydrogen peroxide solution to thesolution under ice-cooling, the resultant mixture was allowed to standovernight at room temperature. The reaction mixture obtained was pouredinto ice water and the crystals precipitated were recovered byfiltration and recrystallized from ethanol to provide 300 mg. of7-chloro-5-oxo-2,3-dihydro-5H-thiazolo-[3,2-b]isoquinoline-1-oxide.

Melting point 216°-217° C.

Elemental analysis for C₁₁ H₈ NO₂ SCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  51.82%   3.04%   5.43%   12.39%                                                                              14.17%                                 Calculated:                                                                           52.08%   3.18%   5.52%   12.64%                                                                              13.97%                                 ______________________________________                                    

EXAMPLE 17 ##STR60##

In 5 ml. of glacial acetic acid was dissolved 650 mg. of7-chloro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline and afteradding 0.8 ml. of a 35% aqueous hydrogen peroxide solution to thesolution, the resultant mixture was refluxed for 2 hours. After thereaction was over, the reaction mixture was cooled and the crystalsprecipitated were recovered by filtration and recrystallized fromglacial acetic acid to provide 500 mg. of7-chloro-5-oxo-2,3-dihydro-5H-thiazolo-[3,2-b]isoquinoline-1,1-dioxide.

Melting point 255°-256° C.

Elemental analysis for C₁₁ H₈ NO₃ SCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  48.73%   2.94%   5.14%   11.93%                                                                              12.99%                                 Calculated:                                                                           48.99%   2.99%   5.19%   11.89%                                                                              13.14%                                 ______________________________________                                    

EXAMPLE 18 ##STR61##

In 10 ml. of o-dichlorobenzene were dissolved 1.6 g. of2-carboxymethyl-5-methoxybenzoic acid and 1.6 g. of 3-aminopropanethiolhydrobromide and after adding 0.8 g. of sodium acetate to the solution,the resultant mixture was heated to 150°-160° C. for 2 hours withstirring. Then, 1.3 g. of p-toluenesulfonic acid was added to thereaction mixture at 140°-150° C. followed by stirring for 30 minutes,the reaction mixture was cooled to room temperature. The precipitatesformed were filtered off and the filtrate was distilled under reducedpressure. The solid residue formed was recrystallized from isopropanolto provide 1.0 g. of8-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 125°-126° C.

Elemental analysis for C₁₃ H₁₃ NO₂ S:

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   62.95%  5.25%       5.49% 12.70%                                     Calculated:                                                                            63.14%  5.30%       5.66% 12.96%                                     ______________________________________                                    

EXAMPLE 19 ##STR62##

In 5 ml. of glacial acetic acid was dissolved 300 mg. of8-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]-isoquinoline andafter adding 0.12 ml. of a 35% aqueous hydrogen peroxide solution to thesolution under ice-cooling, the resultant mixture was allowed to standovernight at room temperature. The reaction mixture obtained was pouredinto ice water and extracted three times each time with 10 ml. ofchloroform. The extracts were combined with each other, washedsuccessively with 1 N hydrochloric acid, a 10% aqueous sodium carbonatesolution, and then water, dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure.

The crude crystals obtained were recrystallized from ethanol to provide220 mg. of8-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide.

Melting point 188°-189° C.

Elemental analysis for C₁₃ H₁₃ NO₃ S:

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   59.01%  4.99%       5.11% 12.12%                                     Calculated:                                                                            59.30%  4.98%       5.32% 12.18%                                     ______________________________________                                    

EXAMPLE 20 ##STR63##

In 5 ml. of glacial acetic acid was dissolved 350 mg. of8-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andafter adding 0.28 ml. of a 35% aqueous hydrogen peroxide solution to thesolution, the resultant mixture was heated to 60°-70° C. for 2 hours.The reaction mixture obtained was cooled and the crystals precipitatedwere recovered by filtration and recrystallized from glacial acetic acidto provide 240 mg. of8-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 215°-216° C.

Elemental analysis for C₁₃ H₁₃ NO₄ S:

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   55.52%  4.66%       4.92% 11.30%                                     Calculated:                                                                            55.90%  4.69%       5.01% 11.48%                                     ______________________________________                                    

EXAMPLE 21 ##STR64##

In 10 ml. of glacial acetic acid were dissolved 1.5 g. of2-carboxymethyl-5-chlorobenzoic acid and 900 mg. of 2-aminopropanethiolhydrochloride and after adding 1.2 g. of sodium acetate to the solution,the resultant mixture was refluxed overnight. After the reaction wasover, the reaction mixture was cooled, poured into ice water andextracted three times each time with 20 ml. of ethyl acetate. Theextracts were combined with each other, washed with a 10% aqueous sodiumcarbonate solution and water, and after drying over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. The crudecrystals obtained were recrystallized from isopropanol to provide 800mg. of7-chloro-3-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline.

Melting point 120°-121° C.

Elemental analysis for C₁₂ H₁₀ NOSCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  57.12%   3.74%   5.57%   12.60%                                                                              14.27%                                 Calculated:                                                                           57.26%   4.00%   5.56%   12.74%                                                                              14.08%                                 ______________________________________                                    

EXAMPLE 22 ##STR65##

In 5 ml. of glacial acetic acid was dissolved 500 mg. of7-chloro-3-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline andafter adding 0.22 ml. of a 30% aqueous hydrogen peroxide solution to thesolution under ice-cooling, the resultant mixture was allowed to standfor 48 hours at room temperature. The reaction mixture obtained waspoured into ice water and extracted three times each time with 10 ml. ofchloroform. The extracts were combined with each other, washed with a10% aqueous sodium carbonate solution and water, dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The crude crystals thus obtained were recrystallized fromethanol to provide 250 mg. of7-chloro-3-methyl-5-oxo-2,3-dihydro-5H-thiazolo-[3,2-b]isoquinoline-1-oxide.

Melting point 171°-172° C.

Elemental analysis for C₁₂ H₁₀ NO₂ SCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  53.85%   4.01%   4.87%   11.65%                                                                              12.93%                                 Calculated:                                                                           53.83%   3.76%   5.23%   11.98%                                                                              13.24%                                 ______________________________________                                    

EXAMPLE 23 ##STR66##

In 5 ml. of glacial acetic acid was dissolved 640 mg. of7-chloro-3-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline andafter adding 0.6 ml. of a 30% aqueous hydrogen peroxide solution to thesolution, the resultant mixture was refluxed for 2 hours. After thereaction was over, the reaction mixture was cooled and the crystalsprecipitated were recovered by filtration and recrystallized fromglacial acetic acid to provide 290 mg. of7-chloro-3-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1,1-dioxide.

Melting point 226°-227° C.

Elemental analysis for C₁₂ H₁₀ NO₃ SCl:

    ______________________________________                                        C            H       N         S     Cl                                       ______________________________________                                        Found:  50.59%   3.84%   4.96%   11.33%                                                                              12.26%                                 Calculated:                                                                           50.80%   3.55%   4.94%   11.30%                                                                              12.50%                                 ______________________________________                                    

EXAMPLE 24 ##STR67##

In 10 ml. of o-dichlorobenzene were dissolved 1.0 g. of2-carboxymethyl-5-hydroxybenzoic acid and 1.1 g. of 3-aminopropanethiolhydrobromide and after adding 520 mg. of sodium acetate to the solution,the resultant mixture was heated to 150°-160° C. with stirring. Then,880 mg. of p-toluenesulfonic acid was added to the reaction mixture at120°-130° C. followed by stirring for 30 minutes, the reaction mixturewas distilled off under reduced pressure. The residue formed was pouredin water and crystals thus precipitated were recovered by filtration andrecrystallized from isopropanol to provide 500 mg. of8-hydroxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 230°-231° C.

Elemental analysis for C₁₂ H₁₁ NO₂ S:

    ______________________________________                                               C     H           N       S                                            ______________________________________                                        Found:   61.64%  4.61%       5.87% 13.85%                                     Calculated:                                                                            61.78%  4.75%       6.00% 13.74%                                     ______________________________________                                    

EXAMPLE 25 ##STR68##

In 5 ml. of o-dichlorobenzene were dissolved 645 mg. of2-carboxymethyl-5-chlorobenzoic acid and 185 mg. of 2-aminoethanol andafter adding 100 mg. of p-toluenesulfonic acid to the solution, theresultant mixture was heated to 150°-160° C. for 3 hours with stirring.The reaction mixture was distilled off under reduced pressure and theresidue formed was extracted with 30 ml. of benzene. The extract wassuccessively washed with 1 N hydrochloric acid, a 10% aqueous sodiumcarbonate solution, and water, dried over anhydrous sodium sulfate, andthen the solvent was distilled off under reduced pressure. The residueformed was applied to a silica gel column chromatography, purified usingchloroform as an eluting solution and the crude crystals obtained werefurther recrystallized from ethanol to provide 170 mg. of7-chloro-5-oxo-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline.

Melting point 138°-139° C.

Elemental analysis for C₁₁ H₈ NO₂ Cl:

    ______________________________________                                               C     H           N       Cl                                           ______________________________________                                        Found:   59.37%  3.56%       6.14% 16.25%                                     Calculated:                                                                            59.61%  3.64%       6.32% 16.00%                                     ______________________________________                                    

EXAMPLE 26 ##STR69##

In 5 ml. of o-dichlorobenzene were dissolved 640 mg. of2-carboxymethyl-5-chlorobenzoic acid and 225 mg. of 3-aminopropanol andafter adding 100 mg. of p-toluenesulfonic acid to the solution, theresultant mixture was refluxed for 2 hours with stirring. After thereaction was over, the reaction mixture was distilled under reducedpressure and the residue formed was extracted with 30 ml. of benzene.The extract was successively washed with 1 N hydrochloric acid, a 10%aqueous sodium carbonate solution, and water, dried over anhydroussodium sulfate, and then the solvent was distilled off under reducedpressure. The residue formed was applied to a silica gel columnchromatography, purified using chloroform as an eluting solution, andthe crude crystals obtained were further recrystallized from ethanol toprovide 190 mg. of8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-oxazino[3,2-b]isoquinoline.

Melting point 115°-116° C.

Elemental analysis for C₁₂ H₁₀ NO₂ Cl:

    ______________________________________                                               C     H           N       Cl                                           ______________________________________                                        Found:   61.52%  4.16%       5.94% 15.14%                                     Calculated:                                                                            61.16%  4.28%       5.94% 15.04%                                     ______________________________________                                    

EXAMPLE 27 ##STR70##

To 20 ml. of o-dichlorobenzene were added 2.2 g. of2-carboxymethylbenzoic acid, 0.82 g. of sodium acetate, and 1.72 g. of3-aminopropanethiol hydrobromide. After heating the mixture to 140°-150°C. for 2 hours, 1.9 g. of p-toluenesulfonic acid was added thereto, andthe resultant mixture was heated to the same temperature as above forone hour. Then, after cooling the reaction mixture, the solvent wasdistilled off under reduced pressure and after adding water to theresidue obtained, the product was extracted twice each time with 50 ml.of chloroform. The extracts were combined with each other, washed withwater and then a diluted aqueous sodium carbonate solution, and driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure and the residue obtained was applied to a silica gelcolumn chromatography and purified using chloroform as an elutingsolution. The crude crystals (700 mg.) thus obtained were furtherrecrystallized from ethyl acetate to provide 500 mg. of8-nitro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 224°-226° C.

Elemental analysis for C₁₂ H₁₀ N₂ O₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     54.60%    3.93%     10.50%  11.92%                                 Calculated:                                                                              54.95%    3.84%     10.68%  12.22%                                 ______________________________________                                    

EXAMPLE 28 ##STR71##

A mixture of 300 mg. of8-nitro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, 0.26ml. of a 35% aqueous hydrogen peroxide solution, and 5 ml. of aceticacid was refluxed for 1.5 hours. After the reaction was over, thereaction mixture was cooled and the precipitates formed were recoveredby filtration, washed with water, and dried. By recrystallizing theproduct from acetic acid, 190 mg. of8-nitro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxidewas obtained.

Melting point 242°-244° C.

Elemental analysis for C₁₂ H₁₀ N₂ O₅ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     48.65%    3.32%     9.39%   10.70%                                 Calculated:                                                                              48.97%    3.40%     9.52%   10.88%                                 ______________________________________                                    

EXAMPLE 29 ##STR72##

To 20 ml. of o-dichlorobenzene were added 2.3 g. of2-carboxymethyl-5-dimethylaminobenzoic acid, 0.9 g. of sodium acetate,and 1.8 g. of 3-aminopropanethiol hydrobromide and after heating themixture to 140°-150° C. for 2 hours and adding thereto 2.7 g. ofp-toluenesulfonic acid, the resultant mixture was heated to the sametemperature as above for one hour. Then, the reaction mixture was cooledand then the solvent was distilled off under reduced pressure. Afteradding water to the residue, it was extracted twice each time with 50ml. of chloroform. The extracts were combined with each other, washedwith water, and dried over anhydrous magnesium sulfate. Thereafter,chloroform was distilled off under reduced pressure and the residueformed was applied to a silica gel column chromatography and purifiedusing chloroform as an eluting solution. The crude crystals obtainedwere further recrystallized from cyclohexane to provide 400 mg. of8-dimethylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 141°-142° C.

Elemental analysis for C₁₄ H₁₆ N₂ OS:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     64.44%    6.20%     10.61%  12.75%                                 Calculated:                                                                              64.59%    6.19%     10.76%  12.32%                                 ______________________________________                                    

EXAMPLE 30 ##STR73##

By following the same procedure as in Example 29 using 2.3 g. of2-carboxymethyl-5-methylaminobenzoic acid and 1.8 g. of3-aminopropanethiol.hydrobromide, 300 mg. of8-methylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinolinewas obtained.

Melting point 171°-172° C.

Elemental analysis for C₁₃ H₁₄ N₂ OS:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     63.28%    5.72%     11.27%  12.80%                                 Calculated:                                                                              63.39%    5.73%     11.37%  13.02%                                 ______________________________________                                    

EXAMPLE 31 ##STR74##

Hydrogen gas was blown into a mixture of 0.5 g. of8-nitro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, 100 mg.of 5% pd/c, and 20 ml. of chloroform. After the absorption of hydrogengas stopped, the reaction mixture was filtered and the filtrate wasdistilled under reduced pressure. The residue formed was recrystallizedfrom benzene-hexane to provide 170 mg. of8-amino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 151°-152° C.

Elemental analysis for C₁₂ H₁₂ N₂ OS:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     62.01%    5.27%     12.05%  13.75%                                 Calculated:                                                                              62.04%    5.21%     12.06%  13.80%                                 ______________________________________                                    

EXAMPLE 32 ##STR75##

A mixture of 550 mg. of8-dimethylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline,10 ml. of acetic acid, and 0.41 ml. of a 35% aqueous hydrogen peroxidesolution was stirred at 20°-30° C. After one hour, the reaction mixturewas filtered and after adding 10 ml. of water to the filtrate, anhydroussodium carbonate was added to it to make the filtrate basic. Theprecipitates formed were recovered by filtration and dried. Byrecrystallizing from benzene-hexane, 300 mg. of8-dimethylamino-6-oxo-3,4-dihydro-2H,6-1,3-thiazino[3,2-b]isoquinoline-1-oxidewas obtained.

Melting point 190°-192° C.

Elemental analysis for C₁₄ H₁₆ N₂ O₂ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     61.09%    5.88%      9.95%  11.80%                                 Calculated:                                                                              60.85%    5.84%     10.14%  11.60%                                 ______________________________________                                    

EXAMPLE 33 ##STR76##

In 2 ml. of acetic acid was dissolved 250 mg. of7-dimethylamino-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinolinefollowed by cooling and after adding 0.1 ml. of a 35% aqueous hydrogenperoxide solution to the solution, the resultant mixture was stirred for20 hours at room temperature. After the reaction was over, the reactionmixture obtained was poured in ice water and after making the reactionmixture alkaline with sodium carbonate, the product was extracted twiceeach time with 50 ml. of ethyl acetate. The extracts were combined witheach other, washed with water, and dried. The solvent was distilled offunder reduced pressure and the residue obtained was recrystallized frombenzene-hexane to provide 80 mg. of7-dimethylamino-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1-oxide.

Elemental analysis for C₁₃ H₁₄ N₂ O₂ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     59.44%    5.30%     10.30%  11.99%                                 Calculated:                                                                              59.52%    5.38%     10.68%  12.22%                                 ______________________________________                                    

EXAMPLE 34 ##STR77##

In 12 ml. of acetic anhydride were dissolved 1.0 g. of7-chloro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline-1-oxide and asmall amount of anhydrous sodium acetate and the solution thus formedwas refluxed for 12 hours. The reaction solvent was distilled off underreduced pressure and after adding to the solid residue thus formed 12ml. of concentrated sulfuric acid, the mixture was allowed to stand for30 minutes. The reaction mixture was poured in ice water and thecrystals precipitated were recovered by filtration and recrystallizedfrom a mixture of cyclohexane and ethyl acetate (4:1 by volume ratio) toprovide 380 mg. of 7-chloro-5-oxo-5H-thiazolo[3,2-b]isoquinoline.

Melting point 172°-173° C.

Elemental analysis for C₁₁ H₆ NOSCl:

    ______________________________________                                               C      H        N        S      Cl                                     ______________________________________                                        Found:   55.83%   2.37%    5.79%  13.32% 15.34%                               Calculated:                                                                            56.06%   2.57%    5.94%  13.60% 15.04%                               ______________________________________                                    

EXAMPLE 35 ##STR78##

To 5 ml. of glacial acetic acid containing 300 mg. of7-chloro-5-oxo-5H-thiazolo[3,2-b]isoquinoline was added 3.5 ml. of a 35%aqueous hydrogen peroxide solution and the mixture was refluxed for 2hours with stirring. The reaction mixture was poured into ice water andthe solids precipitated were recovered by filtration and recrystallizedfrom ethyl acetate to provide 100 mg. of7-chloro-5-oxo-5H-thiazolo[3,2-b]isoquinoline-1,1-dioxide.

Melting point 254°-255° C.

Elemental analysis for C₁₁ H₆ NO₃ SCl:

    ______________________________________                                               C      H        N        S      Cl                                     ______________________________________                                        Found:   49.18%   2.08%    5.18%  11.95% 13.48%                               Calculated:                                                                            49.36%   2.26%    5.23%  11.98% 13.24%                               ______________________________________                                    

EXAMPLE 36 ##STR79##

While ice-cooling 10 ml. of fuming nitric acid, 2.0 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide wasadded thereto slowly so that the reaction temperature was not over 6° C.After the reaction was over, the reaction product was poured into icewater and extracted twice each time with 50 ml. of chloroform. Theextract was washed with water and a diluted aqueous sodium carbonatesolution, and then dried over anhydrous magnesium sulfate. The solventwas distilled off to provide 430 mg. of a crude product. The product wasrecrystallized from acetic acid to provide 160 mg. of8-nitro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 242°-244° C.

EXAMPLE 37 ##STR80##

In 10 ml. of o-dichlorobenzene were dissolved 1.5 g. of5-carboxy-6-carboxymethyl-1,3-benzodioxole and 1.5 g. of3-aminopropanethiol hydrobromide and after adding 0.72 g. of anhydroussodium acetate to the solution, the resultant mixture was heated to150°-160° C. for 2 hours with stirring. Then, 1.2 g. ofp-toluenesulfonic acid was added to the mixture at 150°-160° C. followedby stirring for 30 minutes. The reaction mixture obtained was cooled toroom temperature and the solids precipitated were recovered byfiltration and washed with 30 ml. of benzene. The filtrate was combinedwith the washings and the mixture was distilled under reduced pressure.The solid residue formed was recrystallized from isopropanol to provide1.5 g. of6-oxo-3,4-dihydro-2H,6H-1,3-dioxolo[g][1,3]-thiazino[3,2-b]isoquinoline.

Melting point 121°-122° C.

Elemental analysis for C₁₃ H₁₁ NO₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     59.39%    4.40%     5.07%   11.94%                                 Calculated:                                                                              59.76%    4.24%     5.36%   12.27%                                 ______________________________________                                    

EXAMPLE 38 ##STR81##

In 7 ml. of glacial acetic acid was dissolved 650 mg. of6-oxo-3,4-dihydro-2H,6H-1,3-dioxolo[g][1,3]-thiazino[3,2-b]isoquinolineand after adding 0.24 ml. of a 35% aqueous hydrogen peroxide solution tothe solution under ice-cooling, the resultant mixture was allowed tostand overnight at room temperature. The reaction mixture was poured inice water and then neutralized with sodium carbonate. The solidsprecipitated were recovered by filtration and recrystallized, afterwashing with water, from ethanol to provide 430 mg. of6-oxo-3,4-dihydro-2H,6H-1,3-dioxolo[g][1,3]-thiazino-[3,2-b]isoquinoline-1-oxide.

Melting point 189°-190° C.

Elemental analysis for C₁₃ H₁₁ NO₄ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     56.69%    3.89%     4.62%   11.31%                                 Calculated:                                                                              56.31%    4.00%     5.05%   11.56%                                 ______________________________________                                    

EXAMPLE 39 ##STR82##

In 10 ml. of glacial acetic acid was dissolved 520 mg. of6-oxo-3,4-dihydro-2H,6H-1,3-dioxolo[g][1,3]-thiazino[3,2-b]isoquinolineand after adding 0.4 ml. of a 35% aqueous hydrogen peroxide solution tothe solution, the resultant mixture was heated to 70°-80° C. for 3hours.

The reaction mixture obtained was poured into ice water and neutralizedwith sodium carbonate. The solids precipitated were recovered byfiltration, washed with water, and recrystallized from glacial aceticacid to provide 100 mg. of6-oxo-3,4-dihydro-2H,6H-1,3-dioxolo[g][1,3]-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 261°-262° C.

Elemental analysis for C₁₃ H₁₁ NO₅ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     52.83%    3.76%     4.82%   10.86%                                 Calculated:                                                                              53.24%    3.78%     4.78%   10.93%                                 ______________________________________                                    

EXAMPLE 40 ##STR83##

A mixture of 1.5 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide, 20 ml.of acetic anhydride, and 100 mg. of sodium acetate was refluxed for 10hours. After cooling, the reaction mixture was poured into 80 ml. ofice-water and extracted twice each time with 50 ml. of ethyl acetate.The extracts were combined with each other, washed with a dilutedaqueous sodium carbonate solution and then water, dried over anhydroussodium sulfate, and then the solvent was distilled off under reducedpressure. The residue obtained was applied to a silica gel columnchromatography and purified using chloroform as an eluting solution toprovide 1.23 g. of oily2-acetoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Elemental analysis for C₁₄ H₁₃ NO₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     60.89%    4.94%     4.92%   11.52%                                 Calculated:                                                                              61.07%    4.76%     5.09%   11.65%                                 ______________________________________                                    

EXAMPLE 41 ##STR84##

A mixture of 500 mg. of2-acetoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, 4 ml.of methanol, and 1 ml. of a 1 N aqueous sodium hydroxide solution wasstirred for 30 minutes at room temperature. Then, the reaction mixtureobtained was poured into 30 ml. of ice water, neutralized with dilutedhydrochloric acid, and extracted twice each time with 30 ml. of ethylacetate. The extracts were combined with each other, washed with water,dried over anhydrous sodium sulfate, and then the solvent was distilledoff under reduced pressure. Thereafter, 300 mg. of the residue obtainedwas recrystallized from ethyl acetate-n-hexane to provide 100 mg. of2-hydroxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 175°-180° C.

Elemental analysis for C₁₂ H₁₁ NO₂ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     61.66%    4.72%     5.69%   13.73%                                 Calculated:                                                                              61.78%    4.75%     6.00%   13.74%                                 ______________________________________                                    

EXAMPLE 42 ##STR85##

A mixture of 1.4 g. of2-acetoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, 45mg. of p-toluenesulfonic acid, and 15 ml. of o-dichlorobenzene washeated to 140°-160° C. for 2 hours. After cooling the reaction mixturethe solvent was distilled off from the reaction mixture under reducedpressure and the residue formed was dissolved in 100 ml. of ethylacetate. The ethyl acetate solution was washed with water, dried overanhydrous sodium sulfate, and then the solvent was distilled off underreduced pressure. The residue obtained was applied to a silica gelcolumn chromatography, purified using chloroform as an eluting solutionrecrystallized from cyclohexane to provide 600 mg. of6-oxo-4H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 127°-128° C.

Elemental analysis for C₁₂ H₉ NOS:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     66.55%    4.24%     6.27%   14.49%                                 Calculated:                                                                              66.95%    4.21%     6.51%   14.89%                                 ______________________________________                                    

EXAMPLE 43 ##STR86##

A mixture of 250 mg. of 6-oxo-4H,6H-1,3-thiazino[3,2-b]isoquinoline, 3ml. of acetic acid, and 0.2 ml. of a 35% aqueous hydrogen peroxidesolution was heated to 90°-100° C. for 2 hours. After cooling, thereaction mixture obtained was poured into 50 ml. of ice water to depositprecipitates. The precipitates were recovered by filtration andrecrystallized from ethyl acetate-ethanol to provide 180 mg. of6-oxo-4H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point higher than 260° C. (decomp.)

Elemental analysis for C₁₂ H₉ NO₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     58.34%    3.60%     5.56%   13.01%                                 Calculated:                                                                              58.29%    3.67%     5.66%   12.97%                                 ______________________________________                                    

EXAMPLE 44 ##STR87##

In 2 ml. of acetic acid was dissolved 200 mg. of6-oxo-4H,6H-1,3-thiazino[3,2-b]isoquinoline and after cooling thesolution and adding 0.1 ml. of a 35% aqueous hydrogen peroxide solutionto the solution, the resultant mixture was stirred one day at roomtemperature. After the reaction was over, the reaction mixture waspoured into 30 ml. of ice water and extracted twice each time with 30ml. of ethyl acetate. The extracts were combined with each other, washedwith a diluted aqueous sodium carbonate solution and then water, driedover anhydrous sodium sulfate, and then the solvent was distilled offunder reduced pressure. The residue obtained was applied to a silica gelcolumn chromatography, purified using chloroform as an eluting solution,and recrystallized from ethanol to provide 49 mg. of6-oxo-4H,6H-1,3-thiazino-[3,2-b]isoquinoline.

Melting point 161°-163° C.

Elemental analysis for C₁₂ H₉ NO₂ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     62.32%    3.92%     6.06%   13.86%                                 Calculated:                                                                              62.17%    4.03%     5.94%   14.10%                                 ______________________________________                                    

EXAMPLE 45 ##STR88##

a-1. A mixture of 1.6 g. of homophthalic anhydride, 2.19 g. of3-aminopropyl bromide.hydrobromide, 0.82 g. of sodium acetate, and 10ml. of o-dichlorobenzene was refluxed for 1.5 hours. After cooling, thesolvent was distilled off from the reaction mixture obtained underreduced pressure. The residue formed was applied to a silica gel columnchromatography and purified using chloroform as an eluting solution toprovide 1.3 g. of oily N-(3-bromopropyl)homophthalimide.

Nuclear magnetic resonance spectra (CDCl₃): δ: 2.2 (2 H, m), 3.4(2 H,t), 4.0(2 H, S), 4.1(2 H, t), 7.2-8.2(4 H, m).

a-2. A mixture of 1.8 g. of 2-carboxymethylbenzoic acid, 2.19 g. of3-aminopropyl bromide.hydrobromide, 0.82 g. of sodium acetate, and 10ml. of o-dichlorobenzene was heated to 110°-170° C. for 3 hours. Aftercooling the reaction mixture, the precipitates formed were filtered offfrom the reaction mixture and then the solvent was distilled off fromthe filtrate under reduced pressure. The residue formed was extractedwith 50 ml. of ethyl acetate. The extract was successively treated witha diluted aqueous sodium carbonate solution, diluted hydrochloric acid,and water, dried over anhydrous sodium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue obtained was appliedto a silica gel column chromatography and purified using chloroform asan eluting solution to provide 400 mg. of oilyN-(3-bromopropyl)homophthalimide.

b. After blowing hydrogen sulfide gas into a mixture of 1 g. ofpotassium hydroxide, 6 ml. of ethanol, and 5 ml. of water for 45minutes, 1.3 g. of N-(3-bromopropyl)homophthalimide was added to themixture while further blowing hydrogen sulfide gas at 5°-10° C. and thenthe solution was stirred for 3 hours at room temperature. After thereaction was over, the reaction mixture was poured into 50 ml. of coldwater and extracted with 100 ml. of chloroform. The extract was driedover anhydrous sodium sulfate and then the solvent was distilled offunder reduced pressure. The residue obtained was applied to a silica gelcolumn chromatography and purified using a mixture of benzene andchloroform (1:1 by volume ratio) as an eluting solution to provide 400mg. of oily N-(3-mercaptopropyl)homophthalimide.

Nuclear magnetic resonance spectra (CDCl₃): δ: 1,44-1.62(1 H, t),1.8-2.04(2 H, m), 2.4-2.6(2H, m), 4.0-4.8(2 H, t), 4.02(2 H, s),7.2-8.22(2 H, m).

c. A mixture of 112 mg. of N-(3-mercaptopropyl)homophthalimide, 172 mg.of p-toluenesulfonic acid, and 4 ml. of o-dichlorobenzene was heated to120° C. for 30 minutes. After cooling the reaction mixture, the solventwas distilled off from the reaction mixture under reduced pressure andthe residue obtained was extracted with 50 ml. of benzene. The extractwas washed with water, dried over anhydrous sodium sulfate, and then thesolvent was distilled off under reduced pressure. By recrystallizing theresidue thus obtained from isopropyl alcohol, 70 mg. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was obtained.

EXAMPLE 46 ##STR89##

To 50 ml. of liquid ammonia were added 520 mg. of metallic potassium and15 mg. of ferric nitrate and after stirring the mixture for 5 minutes toform potassium amide, 1.5 g. of 6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide was added to the mixturefollowed by stirring for 15 minutes. Then, 2 g. of methyl iodide wasadded to the mixture under cooling followed by stirring for 5 minutesand the reaction temperature raised gradually to room temperature toevaporate of liquid ammonia. Then, the reaction mixture was extractedwith 100 ml. of chloroform and the extract was washed with dilutedhydrochloric acid and dried over anhydrous sodium sulfate. Thereafter,the solvent was distilled off under reduced pressure. The residue formedwas applied to a silica gel column chromatography and purified using amixture of benzene and chloroform (1:1 by volume ratio) as an elutingsolution to provide two kinds of products.

The product obtained from the first product fraction was recrystallizedfurther from benzene - n-hexane to provide 200 mg. of2,2-dimethyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 185°-186° C.

Elemental analysis for C₁₄ H₁₅ NO₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     60.21%    5.29%     4.77%   11.56%                                 Calculated:                                                                              60.63%    5.45%     5.05%   11.56%                                 ______________________________________                                    

Then, the product obtained from the following fraction wasrecrystallized from benzene to provide 700 mg. of2-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 215°-217° C.

Elemental analysis for C₁₃ H₁₃ NO₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     59.09%    4.98%     5.49%   12.20%                                 Calculated:                                                                              59.30%    4.98%     5.32%   12.18%                                 ______________________________________                                    

EXAMPLE 47 ##STR90##

To 40 ml. of liquid ammonia were added 420 mg. of metallic potassium and10 mg. of ferric nitrate and the mixture was stirred for 5 minutes toprovide potassium amide. Then, 1.5 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide wasadded to the mixture followed by stirring for 15 minutes. After furtheradding 1.3 g. of allyl bromide to the reaction mixture under coolingfollowed by stirring for 5 minutes, the reaction temperature was raisedgradually to room temperature to evaporate liquid ammonia. Thereafter,the reaction product was extracted with 100 ml. of chloroform and theextract was washed with diluted hydrochloric acid, dried over anhydroussodium sulfate, and then the solvent was distilled off under reducedpressure. The residue formed was applied to a silica gel columnchromatography and purified using chloroform as an eluting solution toprovide two kinds of products. The product obtained from the firstproduct fraction was recrystallized further from benzene-cyclohexane toprovide 100 mg. of2,2-diallyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 100°-101° C.

Elemental analysis for C₁₈ H₁₉ NO₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     65.56%    5.89%     4.10%   9.71%                                  Calculated:                                                                              65.57%    5.77%     4.25%   9.71%                                  ______________________________________                                    

Then, the product obtained from the following fraction was furtherrecrystallized from cyclohexane to provide 140 mg. of2-allyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 144°-146° C.

Elemental analysis for C₁₅ H₁₅ NO₃ S:

    ______________________________________                                                 C       H         N         S                                        ______________________________________                                        Found:     62.01%    5.06%     4.89%   11.10%                                 Calculated:                                                                              62.23%    5.18%     4.84%   11.06%                                 ______________________________________                                    

EXAMPLE 48 ##STR91##

A mixture of 2.5 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide and10 ml. of acetic acid was heated to 80°-90° C. and after adding dropwisea mixture of 1.8 g. of bromine and 5 ml. of acetic acid to the mixture,the resultant mixture was heated to 80°-90° C. for 4 hours. Aftercooling, the precipitates formed were recovered by filtration andrecrystallized from acetic acid to provide 1.2 g. of11-bromo-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 240°-250° C. (decompd.)

Elemental analysis for C₁₂ H₁₀ NO₃ SBr:

    ______________________________________                                        C            H        N        S      Br                                      ______________________________________                                        Found:  43.71%   3.00%    4.50%  9.60%  24.21%                                Calculated:                                                                           43.90%   3.04%    4.26%  9.76%  24.39%                                ______________________________________                                    

EXAMPLE 49 ##STR92##

A mixture of 0.8 g. of 2-carboxymethyl-5-methylbenzoic acid, 0.72 g. of3-aminopropanethiol.hydrobromide, 0.34 g. of sodium acetate, and 10 ml.of o-dichlorobenzene was heated to 150°-160° C. for 2 hours. Then, 0.8g. of p-toluenesulfonic acid was added thereto and the mixture washeated to 150°-160° C. for one hour. After cooling, the reaction mixturewas filtered and then the solvent was diltilled off under reducedpressure from the filtrate. The residue formed was dissolved in 850 ml.of benzene.

Thereafter, the solution was successively washed with a dilute aqueoussodium carbonate solution and water, dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue obtained was recrystallized from cyclohexane to provide 400mg. of 8-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 89°-90° C.

Elemental analysis for C₁₃ H₁₃ NSO:

    ______________________________________                                               C       H         N         S                                          ______________________________________                                        Found:   67.79%    5.70%     5.75%   13.77%                                   Calculated:                                                                            67.50%    5.66%     6.06%   13.86%                                   ______________________________________                                    

EXAMPLE 50 ##STR93##

By following the same procedure as in Example 49 using a mixture of 240mg. of 2-carboxymethylbenzoic acid, 300 mg. of2-amino-2-methylpropanethiol, 164 mg. of sodium acetate, and 5 ml. ofo-dichlorobenzene, 120 mg. of3,3-dimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline wasobtained.

Melting point 95°-96° C. (recrystallized from n-hexane)

Elemental analysis for C₁₃ H₁₃ NSO:

    ______________________________________                                               C       H         N         S                                          ______________________________________                                        Found:   67.34%    5.60%     5.72%   13.75%                                   Calculated:                                                                            67.50%    5.66%     6.06%   13.86%                                   ______________________________________                                    

EXAMPLE 51 ##STR94##

A mixture of 1 g. of 2-carboxymethylbenzoic acid, 0.5 g. of2-amino-2-methylpropanol, and 5 ml. of o-dichlorobenzene was heated to150°-160° C. for 4 hours. After cooling, the solvent was distilled offfrom the reaction mixture under reduced pressure and the residueobtained was dissolved in 30 ml. of ethyl acetate. Then, the solutionwas successively washed with diluted hydrochloric acid, a diluted sodiumcarbonate solution, and water, dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Byrecrystallizing the residue obtained from cyclohexane, 700 mg. of3,3-dimethyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline wasobtained.

Melting point 91°-92° C.

Elemental analysis for C₁₃ H₁₃ NO₂ :

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      72.21%     6.03%      6.65%                                       Calculated: 72.54%     6.09%      6.51%                                       ______________________________________                                    

EXAMPLE 52 ##STR95##

A mixture of 0.5 g. of α-methyl-2-carboxymethylbenzoic acid, 0.5 g. of3-aminopropanethiol hydrobromide, 0.25 g. of sodium acetate and 3 ml. ofo-dichlorobenzene was heated to 140°-150° C. for one hour with stirring.The reaction mixture obtained was cooled below 100° C. and after addingthereto 0.6 g. of p-toluenesulfonic acid, the mixture was heated to140°-150° C. for one hour. After cooling, 15 ml. of chloroform was addedto the reaction mixture, then the mixture obtained was successivelywashed with 15 ml. of water and 15 ml. of 10% aqueous potassiumcarbonate solution. The chloroform solution obtained was dried overanhydrous sodium sulfate and then the solvent was distilled off underreduced pressure. The crystalline residue was applied to a silica gelcolumn chromatography, purified using chloroform as an eluting solution,and further recrystallized from ethanol to provide 0.38 g. of11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 96°-98° C.

Elemental analysis for C₁₃ H₁₃ NOS

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      67.13%     5.73%      5.75%                                       Calculated: 67.50%     5.66%      6.06%                                       ______________________________________                                    

EXAMPLE 53 ##STR96##

By following the same procedure as in Example 52 using 0.8 g. ofα-benzyl-2-carboxymethylbenzoic acid, 0.55 g. of3-aminopropanethiol.hydrobromide, 0.27 g. of sodium acetate and 0.9 g.of p-toluenesulfonic acid, 6.63 g. of11-benzyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 118°-119° C. (recrystallized from ethanol)

Elemental analysis for C₁₉ H₁₇ NSO:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      74.01%     5.55%      4.56%                                       Calculated: 74.24%     5.57%      4.56%                                       ______________________________________                                    

EXAMPLE 54 ##STR97##

By following the same procedure as in Example 52 using 0.3 g. ofα-phenyl-2-carboxymethylbenzoic acid, 0.18 g. of2-aminopropanethiol.hydrochloride, 0.12 g. of sodium acetate, and 0.3 g.of p-toluenesulfonic acid, 0.16 g. of3-methyl-5-oxo-10-phenyl-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline wasobtained.

Melting point 204°-208° C. (recrystallized from ethanol)

Elemental analysis for C₁₈ H₁₅ NSO:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      73.46%     5.22%      4.81%                                       Calculated: 73.69%     5.15%      4.77%                                       ______________________________________                                    

EXAMPLE 55 ##STR98##

By following the same procdure as in Example 52 using 0.7 g. ofα-phenyl-2-carboxymethylbenzoic acid, 0.58 g. of3-aminopropanethiol.hydrobromide, 0.3 g. of sodium acetate and 0.75 g.of p-toluenesulfonic acid, 0.54 g. of6-oxo-11-phenyl-3,4-dihydro-2H,6H[1,3]thiazino[3,2-b]-isoquinoline wasobtained.

Melting point 234°-235° C. (recrystallized from ethanol)

Elemental analysis for C₁₈ H₁₅ NSO:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      73.52%     5.14%      4.62%                                       Calculated: 73.69%     5.15%      4.77%                                       ______________________________________                                    

EXAMPLE 56 ##STR99##

A mixture of 0.2 g. of α-isopropyl-2-carboxymethylbenzoic acid, 0.2 g.of 3-aminopropanethiol.hydrobromide, 0.1 g. of sodium acetate, and 3 ml.of o-dichlorobenzene was heated to 140°-150° C. for one hour withstirring. The reaction mixture obtained was cooled below 100° C. andafter adding thereto 0.25 g. of p-toluenesulfonic acid, the mixture washeated to 160° C. for 6 hours. Thereafter, by following the sameprocedure as in Example 52, 0.07 g. of11-isopropyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline wasobtained.

Melting point 123°-124° C. (recrystallized from aqueous methanol)

Elemental analysis for C₁₅ H₁₇ NOS:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      69.02%     6.49%      5.18%                                       Calculated: 69.46%     6.61%      5.40%                                       ______________________________________                                    

EXAMPLE 57 ##STR100##

In 2 ml. of acetic acid was dissolved 0.2 g. of11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andafter adding 0.25 g. of a 30% aqueous hydrogen peroxide solution to thesolution, the resultant mixture was heated to 80°-100° C. for 2 hours.The reaction mixture obtained was dispersed in 20 ml. of water and thecrystals precipitated were recovered by filtration and recrystallizedfrom ethanol to provide 0.08 g. of11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 186°-188° C.

Elemental analysis for C₁₃ H₁₃ NO₃ S:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      59.02%     4.85%      5.12%                                       Calculated: 59.30%     4.98%      5.32%                                       ______________________________________                                    

EXAMPLE 58 ##STR101##

In 2 ml. of acetic acid was dissolved 0.3 g. of11-benzyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andafter adding thereto 0.13 g. of a 30% aqueous hydrogen peroxidesolution, the resultant mixture was allowed to stand for one day. Thereaction mixture was dispersed in 20 ml. of water and extracted with 15ml. of ethyl acetate. The extract was washed with 10 ml. of a 10%aqueous potassium carbonate solution, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The crystallineresidue formed was applied to a silica gel column chromatography,purified using chloroform as an eluting solution and furtherrecrystallized from ethanol to provide 0.18 g. of11-benzyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide.

Melting point 147°-148° C.

Elemental analysis for C₁₉ H₁₇ NSO₂

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      70.27%     5.38%      4.12%                                       Calculated: 70.56%     5.30%      4.33%                                       ______________________________________                                    

EXAMPLE 59 ##STR102##

To a mixture of 3 g. of dimethylformamide and 20 ml. of chloroform wasadded dropwise 3 g. of phosphorus oxychloride with stirring underice-cooling and then the mixture was allowed to stand for one hour atroom temperature. Then, 3 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was added to thesolution and the mixture was refluxed for 3 hours. After cooling thereaction mixture, crystals thus precipitated were recovered byfiltration, dissolved in 100 ml. of water, and made alkaline withpotassium carbonate. The crystals precipitated were recovered byfiltration, washed with water, and recrystallized from methanol, afterdrying, to provide 2.4 g. of11-formyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 143°-145° C.

Elemental analysis for C₁₃ H₁₁ NO₂ S:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      63.61%     4.45%      5.59%                                       Calculated: 63.65%     4.52%      5.71%                                       ______________________________________                                    

EXAMPLE 60 ##STR103##

In 20 ml. of methanol was suspended 0.3 g. of11-formyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andafter adding thereto 50 mg. of sodium borohydride followed by stirringfor 10 minutes, the resultant mixture was concentrated under reducedpressure. The residual crystals were recovered, washed with 20 ml. ofwater, and recrystallized from ethanol after drying to provide 0.25 g.of11-hydroxymethyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 166°-168° C.

Elemental analysis for C₁₃ H₁₃ NO₂ S:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      63.00%     5.26%      5.87%                                       Calculated: 63.14%     5.30%      5.66%                                       ______________________________________                                    

EXAMPLE 61 ##STR104##

To a solution of 4.5 g. of a 40% aqueous dimethylamine solution, 5 ml.of acetic acid, 3 ml. of 37% aqueous formaldehyde solution, and 20 ml.of ethanol was added 0.7 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline and the mixturewas refluxed for 16 hours. The reaction mixture formed was concentratedunder reduced pressure and after adding 30 ml. of water to the residue,the product was extracted with 20 ml. of ethyl acetate. The ethylacetate extract was further extracted with 5% hydrochloric acid andafter the aqueous extract was made alkaline with potassium carbonate,the aqueous layer was further extracted with 15 ml. of ethyl acetate.The extract was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue formed was recrystallized fromaqueous ethanol to provide 0.42 g. of11-dimethylaminomethyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.1/2hydrate.

Melting point 62°-64° C.

Elemental analysis for C₁₅ H₁₉ N₂ O_(3/2) S:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      63.23%     6.76%      9.69%                                       Calculated: 63.57%     6.76%      9.88%                                       ______________________________________                                    

EXAMPLE 62 ##STR105##

By following the same procedure as in Example 61 using 3.3 g. of4-methylpiperazine, 6 ml. of acetic acid, 2.5 ml. of a 37% aqueousformaldehyde solution, 20 ml. of ethanol, and 0.6 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, crude crystalswere obtained. The crude crystals were applied to a silica gel columnchromatography, purified using a mixture of chloroform and methanol asan eluting solution, and further recrystallized from ethyl acetate toprovide 0.29 g. of11-[4-methylpiperazinomethyl]-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.

Melting point 150°-151° C.

Elemental analysis for C₁₈ H₂₃ N₃ OS:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      65.37%     7.03%      12.47%                                      Calculated: 65.62%     7.04%      12.75%                                      ______________________________________                                    

EXAMPLE 63 ##STR106##

By following the same procedure as in Example 61 using 2.8 g. ofpiperidine, 4 ml. of acetic acid, 2.5 ml. of a 37% aqueous formaldehydesolution, 20 ml. of ethanol, and 0.6 g. of6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, an oily productwas obtained. The oily product obtained was applied to a silica gelcolumn chromatography, purified using chloroform as an eluting solution,and the oily product obtained was treated with ethanol hydrochloric acidto provide a hydrochloride, which was then recrystallized frommethanol-ether to provide 0.2 g. of11-piperidinomethyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline.hydrochloride.

Melting point 221°-223° C.

Elemental analysis for C₁₈ H₂₃ N₂ ClOS:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      61.35%     6.71%      7.61%                                       Calculated: 61.61%     6.61%      7.98%                                       ______________________________________                                    

EXAMPLE 64 ##STR107##

A mixture of 300 mg. of8-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, 4 ml.of acetic acid, and 0.26 ml. of a 35% aqueous hydrogen peroxide solutionwas heated to 70°-80° C. for 2 hours. After cooling the reactionmixture, it was poured into ice water and the precipitates formed wererecovered by filtration. The precipitates thus obtained wererecrystallized from ethyl acetate to provide 200 mg. of8-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide.

Melting point 219°-221° C.

Elemental analysis for C₁₃ H₁₃ NSO₃ :

    ______________________________________                                               C       H         N         S                                          ______________________________________                                        Found:   59.03%    4.82%     5.04%   12.29%                                   Calculated:                                                                            59.30%    4.98%     5.32%   12.18%                                   ______________________________________                                    

EXAMPLE 65 ##STR108##

By following the same procedure as in Example 13 using 0.32 g. of2-carboxymethyl-4-chlorobenzic acid, 0.37 g. of 3-aminopropanethiolhydrobromide, 0.172 g. of sodium acetate and 0.3 g. of p-toluenesulfonicacid, 0.15 g. of9-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline wasobtained.

Melting point 109°-110° C. (recrystallized from isopropanol)

Elemental analysis for C₁₂ H₁₀ NOSCl:

    ______________________________________                                        C            H        N        S      Cl                                      ______________________________________                                        Found:  57.11%   3.89%    5.38%  12.81% 13.90%                                Calculated:                                                                           57.26%   4.00%    5.56%  12.74% 14.08%                                ______________________________________                                    

EXAMPLE 66 ##STR109##

A mixture of 0.5 g. of α-phenyl-2-carboxymethylbenzoic acid, 0.14 g. of2-aminoethanol and 3 ml. of acetic acid was refluxed for 2 hours, andthen 0.4 g. of p-toluenesulfonic acid was added to the reaction mixturefollowed by further refluxing for one hour. The reaction mixtureobtained was concentrated under reduced pressure and the residueobtained was dissolved in 20 ml. of ethyl acetate, then the solutionobtained was successively washed with 10 ml. of water and 10% aqueouspotassium carbonate solution. The ethyl acetate solution wasconcentrated under reduced pressure. The residue formed wasrecrystallized from ethanol to provide 0.18 g. of5-oxo-10-phenyl-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline.

Melting point 166°-168° C.

Elemental analysis for C₁₇ H₁₃ NO₂ :

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Found:      77.82%     5.31%      4.90%                                       Calculated: 77.55%     4.98%      5.32%                                       ______________________________________                                    

EXAMPLE 67 ##STR110##

By following the same procedure as in Example 18,10-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline wasobtained.

Melting point 117°-118° C. (recrystallized from isopropylalcohol)

EXAMPLE 68 ##STR111##

By following the same procedure as in Example 18,9-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline wasobtained.

Melting point 86°-87° C. (recrystallized from isopropylalcohol-n-hexane)

EXAMPLE 69 ##STR112##

By following the same procedure as in Example 18,11-methyl-7-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinolinewas obtained.

Melting point 122°-123° C. (recrystallized from cyclohexane)

EXAMPLE 70 ##STR113##

By following the same procedure as in Example 20,10-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxidewas obtained.

Melting point 251°-252° C. (recrystallized from ethanol)

EXAMPLE 71 ##STR114##

By following the same procedure as in Example 20,9-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxidewas obtained.

Melting point 256°-257° C. (recrystallized from acetic acid)

EXAMPLE 72 ##STR115##

By following the same procedure as in Example 20,11-methyl-7-methoxy-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxidewas obtained.

Melting point 198°-199° C. (recrystallized from isopropylalcohol)

EXAMPLE 73 ##STR116##

By following the same procedure as in Example 24,7-hydroxy-11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinolinewas obtained.

Melting point 110°-112° C. (recrystallized from isopropylalcohol)

EXAMPLE 74 ##STR117##

By following the same procedure as in Example 20,7-hydroxy-11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxidewas obtained.

Melting point 169°-170° C. (recrystallized from isopropylalcohol)

What is claimed is:
 1. Nitrogen-containing heterocyclic compoundsrepresented by the formula ##STR118## wherein Y represents a sulfuratom, or a group shown by ##STR119## wherein m is 1 or 2; n represents1; R₁ and R₄, which may be the same or different, each represents ahydrogen atom, a lower alkyl group, or a lower alkenyl group; R₂ and R₃,which may be the same or different, each represents a hydrogen atom, ahydroxyl group, a lower alkanoyloxy group, a lower alkyl group or alower alkenyl group; said R₂ and R₃ may further form together a doublebond; R₅ and R₆, Which may be the same or different, each represents ahydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an aminogroup, a lower alkoxy group, a mono or di lower alkylamino group, or alower alkyl group; said R₅ and R₆ may further form together a loweralkylenedioxy group; and R₇ represents a hydrogen atom, a halogen atom,a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, alower alkyl group, a hydroxy lower alkyl group, a di-lower alkylaminolower alkyl group, a pyrrolidino lower alkyl group, a piperidino loweralkyl group, a morpholine lower alkyl group, or a 4-loweralkylpiperazino lower alkyl group;and the pharmacologically acceptablenon-toxic salts thereof.
 2. The compounds as claimed in claim 1 whereinY is a sulfur atom or an ##STR120## group and R₂ and R₃ are a hydrogenatom or a lower alkyl group and the pharmacologically acceptablenon-toxic salts thereof.
 3. The compounds as claimed in claim 1 whereinY is a sulfur atom or an ##STR121## group; n is 1; and R₂ and R₃ are ahydrogen atom or a lower alkyl group and the pharmacologicallyacceptable non-toxic salts thereof.
 4. A compound as claimed in claim 1which is 6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline and thepharmacologically acceptable non-toxic salts thereof.
 5. A compound asclaimed in claim 1 which is6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide and thepharmacologically acceptable non-toxic salts thereof.
 6. A compound asclaimed in claim 1 which is6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxide andthe pharmacologically acceptable non-toxic salts thereof.
 7. A compoundas claimed in claim 1 which is8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline and thepharmacologically acceptable non-toxic salts thereof.
 8. A compound asclaimed in claim 1 which is8-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxideand the pharmacologically acceptable non-toxic salts thereof.
 9. Acompound as claimed in claim 1 which is11-formyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andthe pharmacologically acceptable non-toxic salts thereof.
 10. A compoundas claimed in claim 1 which is11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline andthe pharmacologically acceptable non-toxic salts thereof.
 11. A compoundas claimed in claim 1 which is11-dimethylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinolineand the pharmacologically acceptable non-toxic salts thereof.
 12. Acompound as claimed in claim 1 which is11-methyl-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1,1-dioxideand the pharmacologically acceptable non-toxic salts thereof.